Breast-feeding and the development of cows' milk protein allergy.

Early feeding with cows' milk (CM) may cause cows' milk allergy (CMA). Breast milk contains many immune factors which compensate for the undeveloped defence mechanisms of the gut of the newborn infant. We studied the effect of supplementary CM feeding at the maternity hospital on the subsequent incidence of CMA, the effects of formula and breast feeding on the subsequent immunologic types of CMA, and the importance of immune factors present in colostrum in the immune responses of infants with CMA. In a cohort of 6209 infants, 824 were exclusively breast-fed and 87% required supplementary milk while in the maternity hospital: 1789 received CM formula, 1859 pasteurized human milk, and 1737 whey hydrolysate formula. The cumulative incidence of CMA, verified by a CM elimination-challenge test, was 2.4% in the CM, 1.7% in the pasteurized human milk and 1.5% in the whey hydrolysate group. Among these infants, exposure to CM at hospital and a positive atopic heredity increased the risk of CMA. Of the exclusively breast-fed infants, 2.1% had CMA. Risk factors for the development of IgE-mediated CMA were: exposure to CM at hospital, breast-feeding during the first 8 weeks at home either exclusively or combined with infrequent exposure to small amounts of CM and long breast-feeding. The content of transforming growth factor-beta1 (TGF-beta1) in colostrum from mothers of infants with IgE-mediated CMA was lower than from mothers of infants with non-IgE-mediated CMA. In infants with CMA, TGF-beta1 in colostrum negatively correlated with the result of skin prick test and the stimulation of peripheral blood mononuclear cells to CM, but positively with infants' IgA and IgG antibodies to CM proteins. Feeding of CM formula at maternity hospital increases the risk of CMA, but exclusive breast-feeding does not eliminate the risk. Prolonged breast-feeding exclusively or combined with infrequent exposure to small amounts of CM during the first 8 weeks induces the development of IgE-mediated CMA. Colostral TGF-beta1 may inhibit IgE- and cell mediated reactions and promote IgG-IgA antibody production to CM in infants prone to developing CMA.

Supplementary feeding in maternity hospitals and the risk of cow's milk allergy: A prospective study of 6209 infants.

BACKGROUND: Early feeding with cow's milk (CM) may increase the risk of cow's milk allergy (CMA). OBJECTIVE: We sought to examine prospectively whether supplementary feeding of CM at the maternity hospital would increase the risk when compared with feeding with pasteurized human milk or hydrolyzed formula. METHODS: We studied 6209 unselected healthy, full-term infants, of whom 5385 (87%) required supplementary milk while in the hospital. The infants were randomly assigned to receive CM formula (1789 infants), pasteurized human milk (1859 infants), or whey hydrolysate formula (1737 infants). The comparison group (824 infants) was composed of infants who were exclusively breast-fed. The infants were followed for 18 to 34 months for symptoms suggestive of CMA. The primary endpoint was a challenge-proven adverse reaction to CM after a successful CM elimination diet. RESULTS: The cumulative incidence of CMA in the infants fed CM was 2.4% compared with 1.7% in the pasteurized human milk group (odds ratio [OR], 0.70; 95% confidence interval [CI], 0. 44-1.12) and 1.5% in the whey hydrolysate group (OR, 0.61; 95% CI, 0. 38-1.00). In the comparison group, CMA developed in 2.1% of the infants. Among the infants who required supplementary feeding at hospital, both exposure to CM while in the hospital (OR, 1.54; 95% CI, 1.04-2.30; P =.03) and obvious parental atopy (OR, 2.32; 95% CI, 1.53-3.52; P <.001) increased the risk of CMA. CONCLUSIONS: Our data indicate that feeding of CM at maternity hospitals increases the risk of CMA when compared with feeding of other supplements, but exclusive breast-feeding does not eliminate the risk.

HLA antigens, jejunal morphology and associated diseases in children with dermatitis herpetiformis.

Forty-five Hungarian and Finnish children from 1.5 to 15 years with dermatitis herpetiformis were studied for HLA antigens, jejunal morphology on gluten-containing diet and associated diseases in the patients and their relatives. A strong association with HLA-B8 was found in patients of both nationalities, the relative risks were 12.8 and 9.6, respectively. The Hungarian patients were also typed for HLA-DR locus, and an association with DR3 but not with DR7 was observed. Patients with subtotal villous atrophy had slightly more often HLA-B8 and DR3 than those with milder intestinal lesions. Atopic eczema occurred in 20% of the patients and family history of atopy seemed to have an inverse correlation with HLA-B8 and DR3.

Late mucosal relapse in a boy with coeliac disease and cow's milk allergy.

A case of coeliac disease where exceptionally long gluten challenge was needed to produce mucosal relapse is presented. An initial diagnosis of intestinal cow's milk allergy with total villous atrophy was made at the age of 3.5 months. The lesion healed after the child was put on a diet free of cow's milk and gluten. After 4.3 years on a normal diet his jejunal structure was still normal but at the age of 10.9 years, after 8.7 years of gluten ingestion, total villous atrophy was again observed. On a gluten-free diet the small intestinal structure is completely normal at the age of 17.1 years.

Intestinal cow's milk allergy.

Cow's milk allergy (CMA) is multifaceted disease representing systemic, skin or gastrointestinal reactions to cow's milk (CM) protein. This article shortly reviews the intestinal form of CMA (ICMA). According us the child is allergic to CM when the immunologic reaction to CM is associated with clinical symptoms. The incidence of CMA is 1.3-1.9% in general, but the ICMA only 0.6 pro mille among the children less than six months of age. The majority of infants shows symptoms within a month of starting CM feeding. The majority of children with CMA have gastrointestinal symptoms. Manx of these infants has additionally dermatological symptoms and some respiratory symptoms. The mode of onset is often acute diarrhoea and vomiting, as in acute gastroenteritis. Laboratory findings indicate iron deficiency anemia in 20-70%. Half to two thirds of infants with chronic diarrhoea have moderate to severe steatorrhoea. The morphologic lesion in the gastrointestinal tract in ICMA is widespread, often being present from stomach to rectum. Jejunal lesion is most severe in the proximal part of the intestine and nowadays most patients have only partial villous atrophy or slight changes of the villi. Both the epithelium and the lamina propria of the jejunum are infiltrated with inflammatory cells. The morphology of the small intestine speaks for a strong immune reaction which leads increased destruction of surface epithelial cells. We recommend elimination of CM proteins to the age of 1.5 to 2 years. Most patients tolerate CM by the age of 2 years without symptoms. Prolonged breast-feeding and avoidance of early contact with CM are important in reducing the severity and frequency of CMA.

Dermatitis herpetiformis: jejunal findings and skin response to gluten free diet.

Fifty seven children with dermatitis herpetiformis, 18 from Finland and 39 from Hungary, were studied. Diagnostic criteria included the finding of granular IgA deposits in the skin of all patients. The mean age at onset of the rash was 7 X 2 years and favoured sites were the elbows, knees, and buttocks. Symptoms suggesting small intestinal disease were rare but in 35 (61%) of the children subtotal villous atrophy and in 16 (28%) partial villous atrophy were found on jejunal biopsy. Eighteen children underwent a second biopsy after a mean of 21 months on a gluten free diet; villous height was found to be increased and the intraepithelial lymphocyte count decreased in all these patients. Gluten challenge caused a reversal in the two children who underwent a third biopsy. The effect of the gluten free diet on the rash was examined in Finnish children by observing the daily requirements of dapsone, a drug used to control the rash at the beginning of the diet. Eight (67%) of the 12 children were able to stop taking dapsone after a mean of 11 months on the diet and all three patients treated with diet alone became asymptomatic after three to 6 months on the diet. These results confirm that most children with dermatitis herpetiformis have jejunal villous atrophy, though they rarely have gastrointestinal symptoms. The central role of gluten in childhood dermatitis herpetiformis is evidenced by the fact that a gluten free diet helps the damaged jejunal mucosa to recover and controls the rash even in those children who do not have an abnormal jejunal biopsy.

Mast cells and eosinophils in the jejunal mucosa of patients with intestinal cow's milk allergy and celiac disease of childhood.

We counted the number of granulated mast cells with high iron diamine staining, and the number of eosinophils with hematoxyline-eosin staining, in the lamina propria of the jejunum in 12 untreated patients with intestinal cow's milk allergy (CMA), 47 with celiac disease (CD), and 14 controls. A decreased number of mast cells and an increased number of eosinophils were found in 58% of patients with CMA, and in 60% of those with CD. The number of mast cells showed a significant positive correlation with the villous height, and the number of eosinophils a negative correlation with both the villous height, and the number of mast cells. Appropriate dietary treatment resulted in a rise in the number of granulated mast cells and a decrease in the number of eosinophils in both patient groups.

Feeding the low-birth-weight infant. III. Diet influences bile acid metabolism.

Fasting duodenal bile acid concentrations and conjugation patterns were studied during the first 5 weeks of life in 65 low-birth-weight infants, 31 to 36 weeks of gestational age. One group was fed human milk. Approximately 55% of this milk was pooled, expressed, and pasteurized (62 degrees C for 30 minutes), 35% was similarly treated milk from the infant's own mother, and the remainder (10%) was provided by breast-feeding. The other infants, from 3 days of age, were fed one of three formulas: an adapted formula (F1), F1 supplemented with taurine (F2), or F1 supplemented with taurine and cholesterol (F3). The fasting intraluminal concentration of conjugated bile acids was higher in the infants fed human milk than in the infants fed formulas (F = 30.03, p less than .001) reflecting the higher concentrations of all individual bile acids. No significant increase over time was found in the concentration of total bile acids in any feeding group. Chenodeoxycholic acid concentrations, however, increased significantly over time in the infants fed human milk (r = .286, P less than .05). Thus, in the infants fed human milk, the ratio of cholates to chenodeoxycholates changed from 2.03 to 1.29 (P less than .001), whereas it remained stable (2.61) in the groups fed formula. Tauroconjugated bile acids predominated until at least 5 weeks of life in all the infants fed human milk, F2, or F3. In the infants fed F1, the concentration of glycoconjugates increased and that of tauroconjugates remained stable.(ABSTRACT TRUNCATED AT 250 WORDS)

Cadmium in Finnish breast milk, a longitudinal study.

Electrothermal atomic absorption spectrophotometry was employed to analyse cadmium in breast milk. Twenty breast milk samples were donated by seven mothers during 6 months of lactation. All milk samples represented every feeding during a period of 24 h, having foremilk an hindmilk in equal proportions. The median cadmium concentration in the 1st month was 2.0 micrograms/l (range 1.7-3.1 micrograms/l, 7 samples) and then declined to 1.5 micrograms/l (range 1.3-2.5 micrograms/l, 7 samples) and 1.6 micrograms/l (range 1.2-2.0 micrograms/l, 6 samples) in the 3rd and 6th months, respectively. At the age of 1 and 3 months when the infants were totally breast fed the average weekly intake of cadmium was 2.7 and 1.5 micrograms/kg. This is below the provisional tolerable weekly intake of man, from 6.7 to 8.3 micrograms/kg, proposed by WHO.

HLA antigens and atopy in children with coeliac disease.

HLA antigens and various aspects of atopy were studied in 42 Finnish children and adolescents with coeliac disease, and the results were compared with findings of recent population studies. The HLA associations were as expected: relative risks for coeliac disease in individuals with HLA-B8, DR3, and DR7 were 8 . 0, 18 . 6, and 15 . 0, respectively. Children with coeliac disease were significantly more often atopic than unselected schoolchildren. Atopy was significantly more frequent and the onset of coeliac disease later for B8/DR3- patients than B8/DR3+ patients. There was no obvious relation between DR7 and atopy. It is concluded that atopy predisposes to coeliac disease partly independently of the HLA-DR3 associated disease susceptibility gene(s), and that different mechanisms may operate in the pathogenesis in coeliac disease patients with and without atopy.

Congenital lactase deficiency. A clinical study on 16 patients.

There are at least 20 rare autosomal recessive disorders that are excessively common in Finland of which congenital lactase deficiency is one. During the last 17 years we have found 16 cases. In each case the mother noted watery diarrhoea, generally after the first feed of breast milk, and at the latest, by age 10 days. The lactose malabsorption was verified at a mean age of 36 (range 3-90) days, by which time the infants were dehydrated and 15 of them weighed less than at birth (mean weight for age was -2.8 SDs). On a lactose-free elimination diet (a group of 6 on Nutramigen and a group of 10 on soy-based formula) the children caught up in growth. One infant in each group showed allergic symptoms. While the infants were being breast fed their faeces contained 20 to 80 g/l lactose. In 24 peroral lactose tolerance tests, the greatest rise in blood glucose concentration was 0.8 mmol/l. Only 2 patients showed abnormal absorption when tested within a week of lactose elimination, and in each absorption tests became normal during the elimination period. Slight to partial villous atrophy of the jejunum was present in 4 early specimens, but in later ones the mean villous height was normal. The mean height of the epithelial cells was reduced and there were fewer intraepithelial lymphocytes in patients. The lactase activities in jejunal biopsy specimens were lower than in most patients with acquired lactase deficiency, with some overlap. The maltase and sucrase activities were normal.

HLA antigens in intestinal cow's milk allergy.

The histocompatibility antigens of one hundred patients with a severe form of cow's milk allergy were studied. HLA-A and B locus antigens were identified in all patients, C locus antigens in 62 patients and DR locus antigens in 41 patients. The A, B and C locus antigen frequencies were compared with those of healthy blood donors, and DR locus antigen frequencies with those of healthy unrelated volunteers and cadaver kidney donors. The series included six patients with concomitant coeliac disease, who were treated as a separate group. No statistically significant differences between the patients and controls were observed, but suggestive differences became apparent when the patient group was divided into subgroups according to the presence or absence of certain co-existing conditions, and the severity of the initially observed intestinal lesion. It is concluded that several factors contribute to the pathogenesis of intestinal cow's milk allergy, and that in some cases genes linked to the HLA region may play a role.

Longitudinal study on the dietary selenium intake of exclusively breast-fed infants and their mothers in Finland.

The dietary selenium intakes of a group of 13 lactating women living in the Helsinki metropolitan area and those of their 10 exclusively breast-fed infants were studied twice during the course of lactation. The first survey period of the women ranged from 6 to 8 weeks post-partum and the second from 17 to 22 weeks post-partum. The selenium intakes of the infants were determined at 1 and 3 months post-partum. In addition, the concentrations of selenium in the breast milk of four of the mothers were determined 6 months post-partum. Milk samples were collected by a method eliminating errors due to diurnal variations and variations during a single feeding. The validity of the analytical method employed was confirmed by means of an interlaboratory collaboration. The level of selenium concentration in the breast milk fell significantly (P less than 0.0005) from 10.7 +/- 1.6 micrograms/l at 1 month of lactation to 5.8 +/- 1.2 micrograms/l at 3 months of lactation, but remained at that level for up to 6 months of lactation (5.6 +/- 0.4 micrograms/l). The total dietary selenium intake of the infants fell significantly (P less than 0.0005) from 8.0 +/- 1.8 micrograms/d to 4.7 +/- 1.1 micrograms/d at 1 and 3 months post-partum, respectively. The mean maternal dietary selenium intake was 36 +/- 13 micrograms/d during the first survey period and 30 +/- 12 micrograms/d during the second survey period.(ABSTRACT TRUNCATED AT 250 WORDS)

Maternal diet and fatty acid pattern of breast milk.

The effect of habitual maternal diet on the fatty acid composition of breast milk was evaluated by conducting a dietary survey of lactating mothers and by analyzing their breast milk samples. The mean energy intake of the mothers was 9.8 MJ during the first survey week (20 mothers, 6-8 weeks post partum) and 8.6 MJ during the second survey week (13 mothers, 17-22 weeks post partum). Protein, fat and carbohydrate intake comprised 16%, 39% and 45% of the total energy intake, respectively. The breast milk samples contained 3.8% fat. Half of the fatty acids of the diets and breast milk were saturated (S), and one third were monoenoic. Polyunsaturated (P) fatty acids comprised 15% in the diets and 13% in the breast milk. The average P/S ratio was 0.3 both in the diets and breast milk samples. Carbohydrate intake correlated negatively (p less than 0.05) with arachidic acid of breast milk, and both protein and fat intakes correlated positively (p less than 0.05) with palmitic acid of breast milk. The maternal diet had no effect on the total fat content of breast milk. A positive correlation was found between the saturated (p less than 0.05) and polyunsaturated (p less than 0.01) fatty acids of maternal diet and breast milk. As to the single fatty acids, the only significant correlation was found with linoleic acid (p less than 0.01). However, the variation of linoleic acid intake explained only about 27% of the variation occurring in the breast milk.

Morphometric study of the jejunal mucosa in various childhood enteropathies with special reference to intraepithelial lymphocytes.

A morphometric study of intraepithelial (IE) lymphocytes per 100 epithelial cells, villous heights (VH), crypt depths (CrD), and epithelial cell heights (ECH) was made on jejunal specimens of 17 patients with cow's-milk allergy (CMA), 52 with celiac disease (CD), seven with congenital lactase deficiency (CLD), four with acrodermatitis enteropathica (AE), four with giardiasis, and four with dermatitis herpetiformis (DH). The aim of this study was to investigate how the morphometric parameters correlate with each other. All cases with CMA, CD, and DH had villous atrophy with hyperplasia of the crypts, both signs being more severe in cases with CD and DH than with CMA. IE lymphocyte infiltration was more intense in specimens of patients with CD and DH (mean 76.0), than those with CMA (mean 62.5). The ECH were equally reduced in patients with CD and CMA. In a follow-up specimen at 1 year and 10 months for CD patients and 11 months for CMA patients the inflammation was reduced, and the VH were increased but still differed from the controls. In CLD cases the morphology of the villi and crypts of the jejunum was quite normal, with no IE lymphocyte infiltration; ECH were reduced. Minor morphological changes were seen in the specimens of patients with AE and giardiasis. In the whole study group there was a significant linear correlation, either positive or negative, between all variables measured (IE lymphocytes, VH, CrD, and ECH).

Semi-quantitative analysis of immunoglobulins and complement fractions 3 and 4 in the jejunal mucosa in coeliac disease and in food allergy in childhood. Immunohistochemical study by light and electron microscopy.

Immunoglobulins A, M, G and E and complement fractions 3 and 4 in jejunal biopsy specimens of 14 children were stained by the peroxidase-labelled antibody technique and studied in light and electron microscopy. In addition, cryostat sections were stained with FITC-conjugated anti-C3,-C4 and -IgE sera. Five patients had coeliac disease, three intestinal cow's milk or rye allergy, three eczema due to food allergy, and in three patients, who served as controls, intestinal and immunological diseases were excluded. This study showed that increased amounts of IgA and IgM both in coeliac disease and in food allergy are produced by the plasma cells in the lamina propria of the jejunum and are secreted into the gut through the epithelial cells in a similar manner as in the morphologically normal intestine. The amount of IgG produced locally or derived from serum, was increased in coeliac disease. IgE-producing cells were rare in all patients. No deposits of complement were seen in the basement membranes or epithelial cells.

Morphometric and immunohistochemical study of jejunal biopsies from children with intestinal soy allergy.

A morphometric and immunohistochemical restudy was made of jejunal biopsy specimens from 5 patients with soy allergy and the results obtained were compared to those from specimens taken before soy feeding and to those at a later time. All the patients had had previous cow's milk allergy with malabsorption. Gastrointestinal symptoms presented within two weeks of starting the soy based formula but in two patients the symptoms were mild and these patients were able to continue soy feeding. Jejunal biopsy specimens taken within 3 days from the reaction to soy showed villous atrophy associated with crypt hyperplasia and an increased cell renewal rate. Also, these specimens showed an inflammatory reaction in the lamina propria and in the epithelium, and the numbers of IgA- and IgM-containing cells were increased. Later, when the soy proteins were eliminated, the morphology of the jejunum improved and the cell numbers were reduced to normal. The intestinal damage and the local immune reaction caused by soy proteins are similar to those seen in cow's milk allergy with malabsorption. The immunological mechanisms operating in these diseases are thought to be the cause of these changes.

Changing pattern of cow's milk intolerance. An analysis of the occurrence and clinical course in the 60s and mid-70s.

The rapid changeover to commercial adapted infant formulae which took place in Finland between 1973 and 1975 was studied as a factor in the occurrence of severe intestinal cow's milk intolerance (CMI). Of infants treated for CMI in 1962-73, ninety-three percent (25/27) were on homemade or unadapted formulae. The admission rate for CMI in these years was 0.22/1 000 liveborn infants breast fed less than six months. During 1974-77 the corresponding figure was 0.56, with 85% of the patients (18/26) on adapted cow's milk formulae. The patients treated before 1974 had a longer symptomatic period before admission, greater growth retardation and more severe intestinal damage than those seen during and after 1974. This is believed to reflect mainly the increasing awareness of CMI on the part of both laymen and the medical profession. In the history of 2/3 of the patients at least one of the following conditions was noted: non-breast feeding, infectious gastroenteritis, praematurity, 21-trisomy, prior intra-abdominal surgery, Hirschsprung's disease, and atopic disease in family members. The long follow-up averaging over four years revealed four patients with coeliac disease. In one of these the proximal jejunal mucosa was normal after two years on gluten-containing diet, but he showed a mucosal relapse as late as between 2 to 4 years on normal diet.

Cell kinetics in the jejunal crypt epithelium in malabsorption syndrome with cow's milk protein intolerance and in coeliac disease of childhood.

Cell kinetics in the proximal jejunal epithelium were studied by the methods of Cairnie et al. and Wright et al. Seventeen children with untreated malabsorption syndrome and cow's milk protein intolerance (CMI) and 12 of these on a cow's milk free diet were compared with 47 children with untreated coeliac disease, with 15 of these on a gluten free diet, and with 15 controls. The total number of cells in the crypts of the patients with CMI was 1.8 times (P less than 0.001) and in patients with coeliac disease 2.4 times (P less than 0.001) that seen in the controls. During the elimination diet the total number of cells in the crypts returned to the level seen in the controls. The mitotic indices, both crude and corrected, were significantly higher (P less than 0.001) in untreated patients with CMI and those with coeliac disease than in the controls. During dietary treatment the indices fell, but not quite to the level of the controls. These small differences between the two groups may be due to the difference in the causative agents or to the different ages of the patients.

Atypical intestinal alpha-chain disease evolving into selective immunoglobulin a deficiency in a Finnish boy.

The clinical course of alpha-chain disease in a Finnish boy is described. The disease presented with growth retardation and gastrointestinal symptoms at age 10 yr. Tests performed between the ages of 15 and 21 yr showed varying intestinal involvement including the large bowel, ileum, and distal jejunum. Alpha-chain disease protein was present in serum in fluctuating concentrations for at least 5 yr; it was produced by plasmacytoid cells found in the affected parts of the large bowel mucosa. The patient was treated with sulfasalazine and melphalan, but it is not clear that the clinical remission and the subsequent disappearance of the alpha-chain disease protein should be ascribed to this treatment. Concomitant with the normalization of the condition, a selective immunoglobulin A deficiency became apparent. The possibility is raised that an immunoglobulin A deficiency could have been the original defect in the patient, predisposing to intestinal infections; topical overstimulation of a defective immunoglobulin A system due to impaired mucosal defense might thus have explained the emergence of alpha-chain disease cells in the gut.